STAT3 Regulation of Citrate Synthase Is Essential during the Initiation of Lymphocyte Cell Growth

Abstract

Citrate is a required carbon precursor for de novo fatty acid and membrane lipid synthesis. However, the pathways regulating intracellular citrate, particularly during the initial transition from a resting state to cell growth, remain unclear. Here, we show that STAT3 is among the first signaling events activated in resting lymphocytes following growth factor stimulation. During this period, the inhibition of STAT3 blocks the expression of citrate synthase (CS) and reduces the levels of intracellular citrate. As a consequence of CS loss and the reduction in citrate, cells are unable to grow or proliferate in response to extracellular growth factors. These effects were due to STAT3-dependent transcriptional regulation of CS, as exogenous addition of citrate could restore fatty acid synthesis, cell growth, and proliferation. Taken together, our studies reveal that transcription-dependent control of CS is essential for regulating the initiation of cell growth.

STAT3 in Tumor-Associated Myeloid Cells: Multitasking to Disrupt Immunity

“…However, such TLR-induced metabolic transition and DC activation can be effectively abrogated in the presence of IL-10 and likely mediated by STAT3 [ 25 , 68 , 69 ]. As recently shown in lymphocytes, STAT3 can prevent the expression of the citrate synthase, thereby interrupting a key step in the synthesis of fatty acids and preventing cell growth [ 70 ]. Thus, STAT3 plays a gatekeeper role for the metabolic transition of DC in response to immunostimulation.…”

Citrate chemistry and biology for biomaterials design

“…In cytosol, the enzyme ATP citrate lyase (ACL) is responsible for converting citrate into Acetyl-CoA, which is the only and direct substrate for lipid biosynthesis, and also is required for histone acetylation induced by either growth factor or differentiation [91]. For instance, increased citrate was required by lymphocyte cells upon stimulation by extracellular growth factors, for fatty acid synthesis during the initiation of lymphocyte cell growth [92], by up-regulation of CS. In some cases cytosol citrate is further exported to extracellular spaces for specialized purposes.…”

“…On the other hand, extracellular citrate can also be taken up via plasma membrane transporter SLC13a5 [94] by specialized cells such as hepatic cells [95], metastatic cancer cells [96] to meet their high energy or high biosynthetic demands. Exogenous addition of citrate can be also consumed by activated lymphocyte cells for fatty acid synthesis to meet the demand of cell growth [92]. …”

The Non-canonical Role of Metabolic Enzymes in Immune Cells and Its Impact on Diseases

“…Interestingly, in addition to metabolic functions, the CS protein from Toxoplasma gondii promoted the expression of IL-10, TGF-β, IL-1β, and TNF-α and decreased the proliferation of murine macrophages [137]. In adaptive immune system cells, CS is involved in the growth and proliferation of lymphocytes, which, when stimulated with IL-3, activate STAT3, so it depends on CS and promotes cell growth, CS-deficient cells decrease their growth and proliferation, and these effects are restored with the addition of exogenous citrate [43], CS is a candidate as a therapeutic target of inflammatory diseases.…”